Brainstem circuits mediating analgesia involve 3 critical components: the periaqueductal gray (PAG), there rostroventromedial medulla (RVM), and projections from RVM to the spinal cord (SC). The PAG ->RVM- >SC circuit has dominated research design in the pain field for at least 2 decades. It is well known that emotional, motivational and cognitive factors modulate the sensation of pain. However, the circuits by which emotional state and cognitive processing, classically associated with higher order forebrain regions, modulate nociception circuitry and plasticity in descending pain regulatory mechanisms. The role of the forebrain in these changes is unknown. Persistent pain in neonates and adults leads to changes in nociceptive circuitry and plasticity in descending pain regulatory mechanisms. The role of the forebrain in these changes is unknown. This proposal will close these gaps by investigating the circuits and mechanisms by which forebrain nociceptive sites modulates PAG and RVM, and how this regulation is altered by inflammation in neonates and adults. Our anatomical studies show that PAG receives dense inputs from forebrain areas implicated in emotional behavior and analgesia. Three of these sites, the media preoptic area (MPO), central nucleus of the amygdala (CNA), and medial prefrontal context project to both PAG and RVM. The discovery of parallel forebrain projections to PAG and RVM necessitates a shift to experiments that can determine how the forebrain regulates the PAG -> RVM ->SC nociceptive circuit, and how this regulation is modulated by persistent pain. Tract tracing and Fos mapping techniques will test the hypothesis that functionally defined nociceptive sites in MPO, CNA and prefrontal cortex give rise to dense, parallel projects to PAG and RVM, and activate PAG- > RVM and RVM-> SC output neurons. Based on new results in this project and Projects 1 and 2 that inflammation modulates the neurochemistry of brainstem and forebrain nociceptive circuits. Parallel neurophysiological and reversible synaptic blockade techniques will test the hypothesis and descending modulation from these 3 forebrain sites is mediated by parallel actions on the PAG-> RVM and RVM-> SC circuits, and further, that this regulation is altered by inflammation in neonatates and adult animals. The long term goal of this work is to better understand how emotional state and cognitive activities controlled by the forebrain impacts on transient and persistent pain, as well as therapeutic outcomes of persistent pain conditions.